Gastrointestinal (GI) cancers are malignancies of the digestive system, including the esophagus, gallbladder, liver, pancreas, stomach, small intestine, large intestine (colon) and rectum. Nearly 290,000 gastrointestinal cancers will be diagnosed in the United States in 2014, and an estimated 147,000 people will die from some form of this disease.
At the OSUCCC – James, highly specialized GI oncologists, surgeons, researchers and other experts in this discipline collaborate to turn scientific discoveries into innovative treatments tailored to each patient’s individual cancer.
Many of our physicians and researchers are members of the National Comprehensive Cancer Network guideline committees that establish national standards of care for patients across the country. OSUCCC – James physicians also develop clinical trials in collaboration with the National Cancer Institute and other organizations, including industry. Almost every area and stage of GI cancer is covered with a research protocol providing our patients with sound options for treating these cancers.
OSUCCC – James surgeons are nationally recognized for their skill in minimally invasive techniques, as well as in esophageal cancer, colorectal cancer, hepatobiliary and pancreatic cancer, stomach cancer and neuroendocrine tumors throughout the GI tract.
Studies show that clinical outcomes improve when patients are cared for at medical centers that treat a high volume of cases requiring advanced surgical and medical care, especially in cancers of the pancreas, esophagus and rectum. OSUCCC – James surgeons are “high-volume” providers who can manage even the most unusual and complicated cases.
- Examine all molecular aspects of gastrointestinal cancer cells—genetic, epigenetic, RNA/protein, non-coding RNAs and biochemical—and integrate these features to improve cancer risk stratification and to more effectively direct targeted therapies toward each person’s unique cancer
- Develop preclinical and clinical immunotherapeutic approaches that bolster the human immune system’s innate ability to combat gastrointestinal cancer
- Devise targeted therapies designed to thwart gastrointestinal cancer-relevant kinase-signaling pathways
Clinical research on promising investigational treatments for gastrointestinal cancers at the OSUCCC – James is supported by numerous grants both private and public, but particularly from the National Institutes of Health. Here are a few examples.
The Ohio State University as Network Lead Academic Participating Site for the NCI National Clinical Trials Network (NCTN)
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PI: Richard Goldberg, MD
- Provide infrastructure to support Ohio State’s participation in the scientific and clinical research activities of the NCI's NCTN Program as a Network Lead Academic Participating Site (NLAPS)
- Use this support to make scientific discoveries about tumor biology, find better treatments and augment quality of life for patients, thus improving outcomes across the spectrum of cancers affecting adults
- Investigate new therapeutic agents and their toxicities in phase I to II clinical trials
- Evaluate the efficacy and toxicity of novel combinations based on preclinical data to exploit drug combinations more effectively
- Develop multi-modal approaches using surgical, immunological and radiotherapeutic measures in optimal combinations
- Integrate experts in molecular genetics, biochemistry, pharmacology, immunology and biostatistics in the design and execution of therapeutic protocols
- Improve cancer outcomes through discovery and education of pre- and postdoctoral students, nurses, allied medical personnel and physicians
- Understand and exploit tumor heterogeneity to exploit the value of targeted therapies
- Improve management of cancer-related symptoms
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PI: Carlo Croce, MD
- Focus on miR181a/b, miR21, miR25, miR221/222 and miR155 that are overexpressed in HCC, and on miR145, miR215, miR125, miR126, miR192, miR223, and miR122a that are downregulated in HCC
- Assess whether loss of these microRNAs results in overexpression of DNMTs and silencing of tumor-suppressor genes associated with hepatocellular carcinogenesis
- Sequence the 3' UTRs of the DNA methyltransferases DNMT1, DNMT3A and 3B to determine whether mutations in target sequences of microRNAs result in their upregulation
- Assess the role of alterations in several microRNAs in the pathogenesis of HCC to define microRNAs that are suitable targets for therapeutic intervention
- Establish the role of alterations in microRNA expression in the initiation and progression of HCC, and validate microRNAs as targets for therapeutic intervention
Dopamine as a Therapeutic Agent in Stomach Cancer
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PI: Sujit Basu, MD, PhD
- Investigate the role of the non-neuronal stomach dopaminergic system in gastric tumorigenesis
- Elucidate the signaling pathway through which dopamine D5 receptors regulate reactive oxygen species in the stomach
- Determine the therapeutic efficacies of DA D5 receptor agonists in gastric tumorigenesis. Findings from this study will help scientists develop more effective therapies for this disease, which currently has no significant treatment
(PQD6) Muscle Stem Cells and Cancer Cachexia
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PI: Denis Guttridge, PhD
- Explore the hypothesis that events occurring outside the myofiber are not simply consequences of a developing cancer, but instead causal factors that contribute to the pathology of cachexia
- Characterize the myogenic stem cells that contribute to muscle wasting
- Elucidate the role and mechanism of Pax7 deregulation in cancer cachexia
- Gain insight into the mechanisms and therapeutic targets of muscle wasting in cancer and thus broaden an area of cachexia research that has been underexplored
Molecular Mechanism of Diet-Induced Carcinogenesis
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PI: Samson Jacob, PhD
- Test the hypothesis that manipulation of miR-155 levels and treatment with zerumbone (ZER) will inhibit non-alcoholic steatohepatitis (NASH) and hepatocellular carcinogenesis( HCC)
- Elucidate the role of miR-155 in initiation and progression of diet-induced NASH and HCC using miR155KO mice, and identify the underlying mechanism by focusing on miR-155 targets
- Investigate the susceptibility of mice overexpressing miR-155 in hepatocytes or in hepatocytes+Kupffer cells to diet-induced NASH and HCC, and elucidate the underlying mechanism of differential pathogenesis by identifying its cell type-specific targets
- Explore the preventive/therapeutic potential of ZER by assessing its antitumorigenic potential against HCC cells, testing its anti-inflammatory function in mice and elucidating the molecular basis of its function
Tumor-Suppressor Roles of E2F7 and E2F8 in Hepatocellular Carcinoma
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PI: Gustavo Leone, PhD
- Test the hypothesis that E2F8 functions as a transcriptional repressor to control cell cycles and genome ploidy levels, and acts as a tumor suppressor in hepatocellular carcinoma (HCC)
- Understand how the "atypical (E2F8) arm" contributes to the overall E2F transcriptional program in controlling cell cycles and tumor suppression
(OSU-13098) A Phase III Study of Chemotherapy With or Without Algenpantucel-L (HyperAcute®-Pancreas) Immunotherapy in Subjects With Borderline Resectable or Locally Advanced Unresectable Pancreatic Cancer
PI: Tanios Bekaii-Saab, MD
- Combine a chemotherapy regimen that has been shown to improve survival in advanced pancreatic cancer with an experimental pancreatic cancer immunotherapy that stimulates the immune system to recognize and attack the cancer
- Determine whether chemotherapy and immunotherapies can work cooperatively to increase antitumor effects to levels beyond what would be seen with either treatment alone
- Demonstrate that treatment with the immunotherapy increases the time until the tumor progresses or lengthens overall survival when given in combination with the current standard of care therapy for this disease
(OSU-13081) Randomized, Open Label, Phase II Study of MM-111 and Paclitaxel With or Without Trastuzumab in Patients With Traditional and Non-Traditional HER2-Expressing Carcinomas of the Distal Esophagus, Gastroesophageal (GE) Junction and Stomach Who Have Failed Front-Line Metastatic or Locally Advanced Therapy
PI: Tanios Bekaii-Saab, MD
Objective: Determine whether the combination of MM-111 plus paclitaxel and trastuzumab is more effective than paclitaxel and trastuzumab alon
(OSU-11182) A Phase II Study of the Combination of Aflibercept (VEGF-Trap) Plus Modified FOLFOX 6 in Patients With Previously Untreated Metastatic Colorectal Cancer
PI: Richard Goldberg, MD
- Evaluate progression-free survival (PFS) of patients with untreated metastatic colorectal cancer (mCRC) receiving the combination of modified leucovorin calcium, fluorouracil, oxaliplatin (FOLFOX6) (mFOLFOX6) and aflibercept
- Evaluate the objective response rate (complete response [CR] + partial response [PR]) and the disease-control rate (CR + PR + stable disease [SD]), as determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, of patients with untreated mCRC receiving the combination of mFOLFOX6 and aflibercept
- Evaluate overall survival of patients with untreated mCRC receiving the combination of mFOLFOX6 and aflibercept
- Further characterize the safety and toxicity of the combination of mFOLFOX6 and aflibercept, including 60-day all-cause mortality
- Describe patients with mCRC whose disease is rendered resectable as a consequence of therapy with the combination of mFOLFOX 6 and aflibercept
Recent Clinical Research Accomplishments
Statewide Screening Launched by Ohio State Has Lifesaving Potential. The OSUCCC – James has launched a statewide initiative to screen newly diagnosed colorectal cancer patients and their biological relatives for Lynch syndrome, a genetic condition that predisposes individuals to colorectal, uterine and ovarian cancers. The initiative—made possible through money raised by Pelotonia, an annual grassroots bicycle tour that raises money for cancer research at Ohio State—will identify family members who may be at risk of developing these cancers so they can take precautionary measures. The Ohio Colorectal Cancer Prevention Initiative is led by Heather Hampel, a certified genetic counselor at Ohio State. Hampel says about 3 percent of colorectal cancer cases result from Lynch syndrome, which is characterized by inherited mutations in one of four genes for DNA-repair proteins.
Study Indicates Bevacizumab May Benefit Subset of Pancreatic Cancer Patients. A study led by the OSUCCC – James and published in the journal Cancer demonstrated that patients with advanced pancreatic cancer (APCA) and normal baseline serum albumin (b-alb)—a protein made by the liver—benefit from treatment with the drug bevacizumab. The researchers noted that earlier phase III studies of bevacizumab in patients with APCA demonstrated no improvement in outcome and that, to the researchers’ knowledge, there were no validated predictive biomarkers for bevacizumab. However, because emerging data suggested that subsets of patients with APCA may benefit from bevacizumab treatment, the study team evaluated b-alb as a predictive biomarker in a pooled analysis from seven prospective clinical trials of gemcitabine-based therapy with or without bevacizumab. Study findings suggest that future investigations of bevacizumab in patients with APCA should consider selecting those with normal b-alb to maximize potential benefit. Tanios Bekaii-Saab, MD, was principal investigator.
Chemo Technique Should be Considered in Metastatic Neuroendocrine Cancer. A technique called transarterial chemoembolization (TACE), which blocks small blood vessels that sustain tumors, should be considered for treating patients with extrahepatic disease (EHD) from neuroendocrine carcinoma, a study at the OSUCCC – James concluded. The study, published in the Annals of Surgical Oncology, points out that TACE is often used for patients with inoperable neuroendocrine carcinoma liver metastases but notes that metastatic disease is not limited to the liver. Investigators reviewed 192 patients who underwent TACE for large hepatic (liver) tumor burden, progression of liver metastases or poorly controlled carcinoid syndrome due to neuroendocrine carcinoma. They found that, although patients with EHD from neuroendocrine carcinoma experience shorter overall survival after TACE compared with those without EHD, they had similar symptomatic, biochemical and radiographic response to TACE. Mark Bloomston, MD, was principal investigator.
Chemotherapy With Aggressive Surgical Approach Offers Potentially Curative Therapy to Previously Unresectable Pancreatic Cancer. A modified FOLFIRINOX chemotherapy regimen followed by complicated pancreatic surgery resulted in complete resection of more than 50 percent of treated patients who were previously considered not eligible for curative therapy. In an OSUCCC – James study led by Tanios Bekaii-Saab,MD, and Mark Bloomston, MD, and published in the journal Annals of Surgical Oncology, 43 patients with non-metastatic pancreatic cancer involving major blood vessels were treated with a modified regimen of FOLFIRINOX; half also received chemoradiation to help boost response. In the treated patients[SS1] , investigators found that major toxicities were greatly reduced compared to previous reports with FOLFIRINOX, and that 51 percent of tumors could be removed, often without major vascular resection. Progression-free survival was significantly improved when resection was possible compared to those in whom resection was not undertaken (median 18 months vs. 9).
Recent Translational Research Accomplishments
Study Identifies Likely Key Driver of Colorectal Cancer Development and Progression. OSUCCC – James researchers identified a molecule that is a probable driving force in colorectal cancer and may be both an important target for treating this disease and a valuable biomarker of tumor progression. The study of microRNA-135b (miR-135b) in two animal models and human tumors was published in the journal Cancer Cell. The researchers demonstrated that miR-135b is present at abnormally high levels in both mouse and human colorectal (CRC) tumors. They believe the overexpression can be induced by mutations in either well-known oncogenes or tumor-suppressor genes that frequently occur in CRC. Carlo Croce, MD, was principal investigator.
Loss of Tiny Molecule Might Lead to Liver Cancer. A study at the OSUCCC – James showed that loss of a small RNA molecule in liver cells might lead to malignancy, and that restoring the molecule might slow tumor growth and offer a new way to treat the disease. In an animal model, the scientists, led by Kalpana Ghoshal, PhD, examined what happens when liver cells lack a molecule called microRNA-122 (miR-122). They found that when the molecule is missing, the liver develops fat deposits, inflammation and tumors that resemble hepatocellular carcinoma (HCC), the most common form of liver cancer. When the researchers artificially restored miR-122 to nearly normal levels by delivering the miR-122 gene into liver cells, it dramatically reduced the size and number of tumors. The study was published in the Journal of Clinical Oncology with an accompanying commentary.
OSUCCC – James Leads International Pancreatic Cancer Treatment Development Effort. The OSUCCC – James is leading an international pancreatic cancer research effort in collaboration with scientific investigators in Taiwan and Germany to develop targeted therapies and biomarkers for this disease, the fourth-leading cause of cancer death in the United States. Tanios Bekaii-Saab, MD, of the OSUCCC – James, is partnering with doctors at the National Cheng-Kung University in Tainan City, Taiwan, and with former Ohio State researcher Christoph Plass, PhD, at the German Cancer Research Center in Heidelberg, to conduct the initiative. The researchers will work to identify new targets in pancreatic tumors and to develop agents that will strike those targets and halt disease progression.
Research and clinician-scientists at the OSUCCC – James are dedicated to training future generations of scientists. As such, multiple funding mechanisms are available to provide resources needed for advanced training under the mentorship of established senior scientists. This includes National Cancer Institute T32 training grants led by a number of GI researchers, and a T1 mechanism in translational science that is available through Ohio State’s Center for Clinical and Translational Science. And each year, multiple research fellowships are awarded through Pelotonia, a grassroots bicycle tour that raises money for cancer research at the OSUCCC – James.
Medical Oncology Fellowship
The Medical Oncology Fellowship Program at the OSUCCC – James offers a three-year hematology/oncology training program that provides dual board eligibility in hematology and oncology; a two-year medical oncology training program that provides board eligibility in medical oncology; and a two-year hematology training program that provides board eligibility in hematology. All three training tracks offer intensive clinical training (18 months for dual certification and 12 months for oncology and hematology certification) and protected research time.
Surgical Oncology Fellowship
The OSUCCC – James offers one of only 19 surgical oncology fellowships in the United States. Two fellows per year participate in a two-year fellowship that provides an intense inpatient and outpatient surgical experience in solid tumor malignancies. Applicants must be among the top students in their class in residency to be eligible for these competitive positions. Graduates of the program are eligible for certification through the American Board of Surgery in Complex General Surgical Oncology and often go on to academic careers in oncology.